CA1330663C

CA1330663C - Thiazolidinedione derivatives

Info

Publication number: CA1330663C
Application number: CA000580324A
Authority: CA
Inventors: John Michael Berge; Michael Anthony Cawthorne
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1987-10-19
Filing date: 1988-10-17
Publication date: 1994-07-12
Anticipated expiration: 2011-07-12
Also published as: DE3877124T2; IE61028B1; AU2393888A; US5021445A; GR3007168T3; DK578088A; NZ226594A; PT88780B; DK578088D0; EP0313288B1; HK1001174A1; IE883136L; DE3877124D1; JPH01135783A; AU601877B2; ES2053755T3; KR890008129A; EP0313288A1

Abstract

Abstract Novel Compounds A compound of formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein:

R1 and R2 may each represent hydrogen or alkyl providing that at least one of R1 or R2 represents alkyl;
R3 and R4 each represent hydrogen or R3 and R4 together represent a bond;
n represents an integer 1 or 2;
and m represents an integer 1 or 2; a composition containing such a compound and the use of such compounds and compositions in medicine.

Description

,r~!~

c " 1 3 ~

06 This invention relates to a certain class of 07 heterocyclic compounds having activity as 08 a2-adrenoceptor antagonists, to ~ process for preparing o9 such compounds, to pharmaceutical compositions containing such compounds and the use of such compounds 11 and compositions in medicine. ~::

13 European Patent Application, Publication No. 0238753 :~
14 discloses certain heterocyclic compounds of the general lS formula ~A): .

~X N I Cl!z ) 21 m' 23 (A) or a pharmaceutically acceptable salt, ester or amide 26 thereof, wherein:

28 Z represents a residue of a substituted or 29 unsubstituted aryl group, 31 X' represents O or NR wherein R represents a hydrogen 32 atom, a substituted or unsubstituted alkyl group, a 33 substltuted or unsubstituted aryl group, an alkanoyl 34 group substituted or unsubstituted in the alkyl moiety, or an arylalkyl moiety substituted or unsubstituted in 36 the aryl moiety, . ~
. ~

,~

1~3~66~
01 ~ 2 -02 n' represents an integer 1 or 2, 03 m' represents an integer 1 or 2, 04 p represents an integer 2 or 3, and 05 q represents an integer in the range of from 1 to 12.

07 The compounds of ~ormula (A) are disclosed as having 08 good a2-adrenoceptor antagonist activity and to be of 09 potential use for the treatment and/or prophylaxis of hyperglycaemia and/or glaucoma and/or the treatment of 11 hypertension and/or depression and/or for inhibitin~
12 blood platelet aggregation.

14 A small class of heterocyclic compounds that fall within the ~eneral formula (A) but which are not 16 specifically disclosed in EP 0238753 has now 17 surprisingly been discovered to have very good 18 selectivity for the post-~unctional a2-receptor and 19 therefore shows good selectivity from side effects.
These compounds are therefore of particular value in 21 the treatment and/or prophylaxis of hyperglycaemia 22 and/or the treatment of hypertension and/or for 23 inhibitlng blood platelet aggregation.

Accordingly, the present invention provides a compound 26 of formula (I):

29 O~R

32 ¢~ C11 or a pharmaceutically acceptable salt thereof, h.
36 wherein:

1~3~6~

o1 _ 3 _ 02 R1 and R2 may each represent hydrogen or alkyl 03 providing that at least one of Rl or R2 represents 04 alkyl;
05 R3 and R4 each represent hydrogen or R3 and R4 together 06 represent a bond;
07 n represents an integer 1 or 2;
08 and m represents an integer 1 or 2.

Suitably, Rl and R2 each represent alkyl.

12 Preferably, Rl and R2 each represent methyl.

14 Suitably, R3 and R4 each represent hydrogen.
16 Suitably, R3 and R4 together represent a bond.

18 Suitably n represents 1.
19 , .
Suitably m represents 1.

22 In a preferred aspect the present invention provides a 23 compound selected from the group consisting of:

2-(2H-[7-chloro-4-(3-methylbut-2-enyloxy)-1,3-dihydro-26 isoindole]methyl)-4,5-dlhydroimidazole; and 28 2-(2H-~7-chloro-4-(3-methylbutyloxy)-1,3-dihydro-29 isoindole]methyl)-4~5-dihydroimidazole; or a pharmaceutically acceptable salt thereof.

, 32 Suitable pharmaceutically acceptable salts of the 33 compound of formula (I) include acid addition salts.

Suitable pharmaceutically acceptable acid addition 36 salts of compound (I) include pharmaceutically ' ;
.. :~ '' ` . ' `' ~ ' " , , ~

~`: -~
~ 13~0~53 02 acceptable inorganic salts such as the sulphate, 03 nitrate, phosphate, borate, hydrochloride and 04 hydrobromide and pharmaceutically acceptable organic 05 acid addition salts such as acetate, tartrate, maleate, 06 citrate, succinate, benzoate, ascorbate, 07 methane sulphonate, a-ketoglutarate, 08 a-glycerophosphate, and glucose-1-phosphate.
og Preferably the acid addition salt is a hemisuccinate, hydrochloride, a-ketoglutarate, a-glycerophosphate or 11 glucose-l-phosphate, in particular the hydrochloride 12 salt.

14 When used herein the term 'alkyl' includes straight and branched chain alkyl groups containing from 1 to 12 16 carbon atoms, suitably 1 to 6 carbon atoms, such as 17 methyl, ethyl, propyl and butyl yroups.

19 The present invention also provldes a process for the preparation of a compound of formula (I), or a 21 pharmaceutically acceptable salt thereof, which process 22 comprises cyclising a compound of formula (II):

4 "~z3 27 ~ (CH2)n\ NH

8 Cl N--Cilz--C~ (C~2)2 "'12 32 wherein Rl, R2, R3, R4, m and n are as defined in 33 relation to formula ~I); and thereafter, if required, 34 converting a compound of formula (I) into a further compound of formula (I) and/or forming a 36 pharmaceutically acceptable salt thereof.

.
'~

;~

~ 133~66~

~ 01 _ 5 _ ~j 02 A compound of formula ~ may be prepared by reacting ; 03 a compound of formula (III):

0 6 o ~ H

~--(C~12)m ~ 11 Cl ~ III) ~ 12 13 wherein Rl, R2, R3, R4, m and n are as defined in 14 relation to formula (I) and A represents -CN or -CO2R
wherein R rep~esents Cl_6 alkyl, with 1,2-diaminoethane 16 or an activated form thereof.
.~

. : 18 A suitable activated form of 1,2-diaminoethane is the 19 trimethylaluminium adduct of 1,2-diaminoethane. The ~20 activated form of 1,2-diaminoethane is generally the ~21 preferred reagent when A represents -CO2R.

23 Suitably, R represents methyl.
:24 ~25 A compound of formula (III) may be prepared by reacting ~-26 a compound of formula (IV):
:27 31 ¢~C H--C112a 33 Cl (IV) wherein m and n are as defined in relation to formula 36 (I) and A is as defined in relation to formula (III), ~:, H ~

:~;
¦ r~

01 - 6 ~
02 with a compound of formula (v):

04 1 ~1 a5 . X~2 CH - c\- R2 ( V ) 08 wherein Rl, R2, R3 and R4 are as defined in relation to og formula (I~ and X represents a leaving group, preferably a bromine atom.
~ 11 12 The compounds of formula (v) are known compounds or 13 they may be prepared using methods analogous to those 14 used to prepare known compounds.
16 A compound of formula (IV) may be prepared by reacting 17 a compound of formula (VI):

21 ~ N--Cll 24 (VI) ~25 ~26 wherein m and n are as defined in relation to formula -~27 (I) and A is as defined in relation to formula (III) ~`28 and RY represents a hydroxyl protecting group, with a 29 chlorinating agent, and thereafter removing the protecting group RY.

32 A suitable chlorinating agent is any agent capable of 33 inserting a chlorine atom in the required position on 34 the phenyl group of the compound of formula (VI) without affecting the rest of the molecule.

37 Conveniently, sulphuryl chloride may be used as the 38 chlorinating agent.

, .`
., ~ r. ~

.." `' ' ' ': . :

~t ~
133~66~

02 A compound of formula (VI) may be prepared by reacting 03 a compound of formula ~VII):

' 06 ORY
07 ~ (CH2) _ x ( C~2 ) --X
~VII) :~ 11 12 wherein m, n and RY are as defined in relation to 13 formula (VI) and xl represents a leaving group, with 14 a compound of formula ~VIII):
16 H2N-CH2-A (VIII) ~18 wherein A is as defined in relation to formula (III), 19 and thereafter, if required, converting a compound of ` 20 formula (VI) into another compound of formula (VI).

~22 Suitably, xl represents a halogen atom, especially a 23 chlorine or bromine atom, a methanesulphonate group or 24 a p-toluenesulphonate group.
~2~6 Preferably xl represents a bromine atom.

28 Suitable conversions of one compound of formula (VI) ~29 into another compound of formula (VI) include those wherein A, in formula (VI), is converted from one value 31 into another value: for example a compound of formula 32 (VI) wherein A represents nitrile may be converted into 33 a compound of formula (VI) wherein A represents -CO2R, 34 wherein R is as defined in relation to formula (III), by any conventional procedure, for example by 36 hydrolysis to give the corresponding carboxylic acid 37 followed by esterification.

i ~ 1330663 ,, ol Suitable conditions for hydrolysing, the nitrile group 03 include acid conditions, for example using aqueous 04 hydrobromic acid.

06 Suitable conditions for esterification are well known 07 in the art and include treatment with the appropriate 08 alcohol under acidic conditions.
. 09 .
A compound of formula (VII) may be prepared by reaction 11 of a compound of formula (IX):

6 ~ (c~
17 ` (CH2) - OH
18 (IX) wherein m, n and RY are as defined in relation to 21 formula (VI), with a reagent capable of converting a 22 moiety -CH2-OH into a moiety -CH2-Xl.

24 When xl represents a halogen atom, especially a chlorine or bromine atom, a suitable reagent is a 26 halogenating agent such as a phosphorous trihalide.

28 When xl is chlorine a preferred reagent is phosphorous 29 trichloride.
31 When xl is bromine a preferred reagent is phosphorous 32 tribromide.

34 When xl represents a methanesulphonate group, a suitable reagent is a methanesulphonyl halide 36 especially methanesulphonyl chloride.

'.~
, .
'~ . ~ ':
- , : -~`i ' : ~i ~ - 13~66~
. . j ~; o 1 Y
!- ~ 02 When xl represents a p-toluenesulphonate group, a 03 suitable reagent is a p-toluenesulphonyl halide r 04 especially p-toluenesulphonyl chloride.

06 A compound of formula ~IX) may be prepared by reducing 07 a compound of formula (x):

11 ~C~CU2~ --C02R

: 13 (CH ) --CO RS

~X) 17 whereln RY is as defined in relation to formula (VI), r 18 and s each represent either zero or 1 and R5 is a Cl_6 19 alkyl group.
P ~21 A suitable reducing agent is a complex metal hydride ~22 such as lithium aluminium hydride.
~ 23 t ~; 24 A compound of formula (X) may be prepared from a ~25 compound of formula (XI):
~26 ~ 29 ~ ;2~r ~C2R

i i2 ~XI) `~ 34 whereln R5, r and s are as defined in relation to formula (x)~ by converting the hydroxy group therein 36 into a protected hydroxyl group -ORY.

.

., . ,, ~ .~ ~ . .. . . .

~330~
l Suitably, R5 is a methyl group.

04 Suitably, r and s both represent zero.

06 The compounds of formula tXI) are known compounds or 07 they may be prepared using methods analogous to those 08 used to prepare known compounds, for example those 09 disclosed in Helv. Chim. Acta (1931), 14, 511.
11 Suitable conversions of one compound of formula (I) 12 into another compound of formula ~I) include those 13 in which a compound wherein R3 and R4 together 14 represent a bond is coverted into a compound wherein R3 and R4 each represent hydrogen; such a convension may 16 be carried out using any co~ventional procedure such as 17 catalytic reduction.

19 The salts of the compounds of formula (I) may be prepared by the appropriate conventional procedure.

22 The cyclisation of compounds of formula (II) may be 23 carried out under any appropriate conditions, using 24 any suitable solvent system and temperature range appropriate to the particular compound of formula (II), 26 but usually at an elevated temperature.

28 Favourably, for the preparation of a cbmpound of 29 formula ~I), the compound of formula (II) is not isolated from the reaction between the appropriate 31 compound of formula (III) and 1,2-diaminoethane or an 32 activated form thereof, thus the compound of formula 33 (II) is converted in-situ to a compound of formula (I).

Thus, in this favoured form of the process for the 36 preparation of compounds of formula (I), the 37 appropriate compound of formula (III) and ' ~'"' ~' `' ~

`
"~ ` 13~06~
. ``.
. . .~

02 1,2-diaminoethane are reacted together at an elevated 03 temperature, for example within the range 80C to 04 130C, preferably 110C, in any suitable solvent such 05 as toluene; favourably for reactions involving 06 1,2-diaminoethane the reaction is carried out using 07 1,2-diaminoethane as solvent; preferably the reaction 08 is carried out in the presence of a catalytic amount of o9 carbon disulphide; preferably the reaction is carried out under an atmosphere of nitrogen.

12 It will be understood that under the abovementioned 13 conditions the compound of formula (II) initially 14 formed in the reaction between the compound of formula (III) and 1,2-diaminoethane or an activated form 16 thereof; subsequently undergoes cyclisation to give the 17 required compound of formula (I).

19 Accordingly, in an alternative aspect the present invention provides a process for the preparation of a 21 compound of formula (I) which process comprises 22 reacting a compound of formula (III) with 23 1,2-diaminoethane and thereafter if required converting 24 a compound of formula (I) into a pharmaceutically acceptable salt thereof.

27 The reaction between compounds of formulae (IV) and (V) 28 may be carried out in any suitable solvent such as a 29 lower alkyl ketone, for example butanone, at any convenient temperature, suitably at the reflux 31 temperature of the solvent, in the presence of a base, 32 preferably potassium carbonate.

34 The reaction between the compounds of formula (VI) and the chlorinating agent may be carried out under 36 conditions appropriate to the nature of the 37 - chlorinating agent. Thus, for example when the 38 chlorinating agent is sulphuryl chloride, the reaction ~ .~ ,. '. ~ -~ ~ 133~66~
. .;

02 may conveniently be carried out in any suitable 03 solvent, such as dichloromethane or acetic acid, at a 04 low to ambient temperature, conveniently at ambient 05 temperature.

07 A compound of formula (VII) may be prepared from a 08 compound of formula (IX) by using conditions 09 appropriate to the nature of the reagent capable of converting a moiety -CH2-OH into a moiety -CH2-Xl, 11 for example:

13 (i) when xl represents halogen, especially a 14 chlorine or bromine atom and the reagent is a phosphorus trihalide, the reactlon may conveniently be 16 carried out at low to ambient temperature, for example 17 at 5C, in any suitable solvent, such as diethyl ether;

19 (ii) when xl represents a methanesulphonate group or a p-toluenesulphonate and the reagent is a 21 methanesulphonyl halide or a toluenesulphonyl halide 22 respectively, the reaction may be carried out in any 23 suitable solvent, such as pyridine, at a low to ambient 24 temperature, suitably at ambient temperature.
26 The reaction between the compounds of formulae (VII) 27 and (VIII) may conveniently be carried out in an 28 aprotic solvent, such as dimethylformamide, preferably 29 at a slightly elevated temperature, for example at a temperature ln the range of between 20C and 60C.

32 The reduction of the compound of formula (X) is carried 33 out under conditions appropriate to the reducing agent 34 used. Thus, when lithium aluminium hydride is the reducing agent, the reaction may conveniently be 36 carried out in an aprotic solvent, such as diethyl 37 ether, at low to elevated temperature, more usually at ^l,i , ,J F~
.-,.: ~ ,` . `.. , ~ - . :

. ! .
,,`,~ "

02 the reflux temperature of the solvent.

04 In the abovementloned processes any reactive groups may 05 be present as protecting groups. Suitable protecting 06 groups are those used conventionally in the art; for 07 example a suitable hydroxyl protecting group RY is a 08 benzyl group.

The conditions of preparation and removal of the 11 relevant protectlng group are those used conveniently 12 in the art. Thus, when RY is a benzyl group, the 13 compound of formula (XI) may conveniently be reacted 14 with benzyl bromide in the presence of a base such as potassium carbonate, in a solvent such as dimethyl-16 formamide, conveniently at an elevated temperature, for 17 example 80C. Also, when RY is a benzyl group the 18 benzyl group may be removed by using a reagent such as 19 boron trifluoride dimethylsulphide complex.
21 The present invention also provides a compound of 22 fo.mula (I), or a pharmaceutically acceptable salt 23 thereof, for use as an active therapeutic substance.

In a particular aspect, the present invention provides 26 a compound of formula tI), or a pharmaceutically 27 acceptable salt thereof, for use in the treatment 28 and/or prophylaxis of hyperglycaemia.

In a further aspect the present invention provides a 31 compound of formula (I), or a pharmaceutically 32 acceptable salt thereof, for inhibiting blood platelet 33 aygregation.

In a further aspect, the present invention provides a 36 compound of the general formula (I), or a 37 pharmaceutically acceptable salt thereof, for use in ~ ~33~66~
~; ~

C2 the treatment of hypertension in human or non-human 03 mammals.

05 A compound of the general formula (I), or a 06 pharmaceutically acceptable salt thereof, may be 07 admlnistered ~er se or, preferably, as a pharmaceutical 08 composition also comprising a pharmaceutically 09 acceptable carrier.
11 Accordingly, the present invention also provides a 12 pharmaceutical composition comprising a compound of the 13 general formula (I), or a pharmaceutically acceptable 14 salt thereof, and a pharmaceutically acceptable carrier therefor.

17 AS used herein the term ''pharmaceutlcally acceptable~
18 embraces compounds, compositions and ingredients for 19 both human and veterinary use: for example the term ''pharmaceutically acceptable salt'' embraces a 21 veterinarily acceptable salt.

23 The composition may, if desired, be in the form of a 24 pack accompanied by written or printed instructions for use.

27 Usually the pharmaceutical compositions of the present 28 invention will be adapted for oral administration, 29 although composltions for administration by other routes, such as by in~ection and percutaneous 31 absorption, are also envisaged.

33 Particularly suitable compositions for oral 34 administration are unit dosage forms such as tablets and capsules. Other fixed unit dosage forms, such as 36 powders presented in sachets, may also be used.

, ~ i ~ ~!

:~l .~ l33a6~
:
:

02 In accordance with conventional pharmaceutical practice 03 the carrier may comprise a diluent, filler, 04 disintegrant, wetting agent, lubricant, colourant, 05 flavourant or oth0r conventional ad~uvant.

07 Typical carriers include, for example, microcrystalline 08 cellulose, starch, sodium starch glycollate, such as 09 Harry's Cosmeticology published by Leonard Hill Books, Remington's Pharmaceutical Sciences, and the British 11 and US Pharmacopoeias.

13 The compositions of the present invention may be 14 prepared using any conventional process, for example t~ose disclosed in the abovementioned reference texts.

17 Most suitably the composition will be formulated in 18 unit dose form. Such unit dose will normally contain 19 an amount of the active ingredient in the range o~ from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and more 21 especially 0.1 to 250 mg.

23 The present invention ~urther provides a method for the 24 treatment and/or prophylaxis of hyperglycaemia in a 2S human or non-human mammal which comprises administering 26 an effectlve, non-toxic, amount of a compound of 27 formula (I), or a pharmaceutically acceptable salt 28 thereof, to a hyperglycaemic human or non-human mammal 29 in need thereof.

3,1 The present invention further provides a method for the 32 treatment of hypertension in a human or non-human 33 mammal, which comprises administering an effective, 34 non-toxic, amount of a compound of formula (I), or a , 35 pharmaceutically acceptable salt thereof, to an 36 hypertensive human or non-human mammal.

~ 133066~

02 The invention also provides a method for inhibiting 03 blood platelet aggregation in a human or non-human 04 mammal, which method comprises administering an 05 effective non-toxic amount of a compound of formula 06 ~I), or a pharmaceutically acceptable salt thereof, to 07 a human or non-human mammal in need thereof.

09 Conveniently, the active ingredient may be administered as a pharmaceutical composition hereinbefore defined, 11 and this forms a particular aspect of the present 12 invention.

14 In the treatment and/or prophylaxis of hyperglycaemic humans or the treatment of hypertensive humans the 16 compound of the formula (I), or a pharmaceutically 17 acceptable salt thereof, may be taken in doses, such as 18 those described above, one to six times a day in a 19 manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, 21 and more usually about 1 to 1500 mg.

23 In the treatment and/or prophylaxis of hyperglycaemic 24 non-human mammals, especially dogs, the active ingredient may be admlnstered by mouth, usually once or 26 twice a day and ln an amount in the range of from about 27 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 28 mg/kg.

In the inhibition of platelet aggregation in human or 31 non-human mammals, dosage regimes are as indicated 32 above for the treatment and/or prophylaxis of 33 hyperglycaemic human or non-human mammals.

The present inventlon also provides the use of a 36 compound of formula (I), or a pharmaceutically :~. ';
:-: ;

,~1 . . .

`:`` 133~663 02 acceptable salt thereof, for the manufacture of a 03 medicament for the treatment and/or prophylaxis of 04 hyperglycaemia.

06 The present invention further provides the use of a 07 compound of formula (I) or a pharmaceutlcally 08 acceptable salt thereof, for the manufacture of a 09 ~ medicament for the inhlbition of blood platelet aggregation and/or the treatment of hypertension.

12 No toxicological effects are indicated when a compound 13 of formula (I), or a pharmaceutically acceptable salt 14 thereof, is administered in any of the abovementioned dosage ranges.

17 The following Examples illustrate the invention but do 18 not limit lt in any way.
., 19 :

v ~ :
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02 Example l 04 ~-(2H- r 7-Chloro-4-(3-methvlbut-2-envloxv)-1 3-dihvdro-05 isoindolelmethvl)-4,5-dihvdroimidazole 1 ¢~ -- CHz~

14 A mixture of l.Og ~3.6mmol) of 2H-[7-chloro-4-(3-methylbut-2-enyloxy)-1,3-dihydrolsolndole]acetonltrlle, 16 lml ~14.9mmol) of 1,2-diaminoethane and 5 drops of 17 carbon disulphide was heated at 110C under an 18 atmosphere of nltrogen. After 6 hours the mlxture was 19 cooled and partltloned between dlchloromethane and water. The organlc layer was separated, dried and 21 evaporated to yield the crude product.
,.
~ , 23 Recrystalllsatlon from ethyl acetate gave the title 24 compound as an off whlte solld.
26 lH-nmr 6 (CDCl~):

28 7.10 (lH,d); 6.66 (lH,d); 5.42 (lH,t); 4.49 (2H,d);
29 4.03 (4H,s); 3.7-3.5 (lH,broad slgnal, exchanges wlth D20); 3.65 (4H,s); 3.55 (2H,s); 1.78 (3H,s);
33'2 1.72 (3H,s).
. .
: ":

. ~ ~

?; . t ` ' ` -13~6~3 :
`~,01 - 19 -02 Exam~le 2 ~jO 04 2-~2H- r 7-chlQrO-4- 1 3-methYlbutvlOxv ) -1 3-dlhvdro-,., 05 isoindolelmethvl)-4~5-dihvdroimidazole.

~B ~1~

14 The title compound, mp. 128-129, was obtained from l.Og (3.59mmole) of 16 2H-[7-chloro-4-(3-methylbutyloxy)-1,3-17 dihydroisoindole)acetonitrlle and lml (14.9mmole) of 18 1,2-dlaminoethane by an analogous procedure to that 19 descrlbed in Éxample 1.

21 lH_nmr 6 lCDCl~ +D20) 23 7.12 (lH, d); 6.66 ~lH, d); 4.02 (4H, s); 3.98 (lH, d);
24 3.96 (lH, d); 3.65 (4H, 9); 3.59 (2H, s); 1.9-1.7 (lH, m); 1.66 (lH, d); 1.63 (lH, d); 0.95 (6H, d).

~ l .
. ...

13~06~

02 Procedure 1 04 Dimethvl 3-benzvloxY~hthalate 08 ~ CO2CH3 i 10 - C2CH3 13 A mixture of 14.5g (69mmol) of dlmethyl 3-14 hydroxyphthalate, 9.6g (69mmol) of anhydrous potassium carbonate and 8.23ml (69mmol) of benzyl bromide in 50 16 ml of dry dimethylformamide was heated with stirring at 17 80C.

19 After 18 hours the mixture was cooled and poured lnto 500ml of water, and extracted into diethyl ether 21 (3xlOOml). The combined organic extracts were dried 22 and evaporated to yleld the crude compound as an oil.
23 Chromatography over silica gel elutlng with 24 hexane/dlethyl ether (0->s0%) ~ave the title compound as an oil.

27 lH-nmr 6 ~CDCl~):

29 7.7-7.0 (8H,m); 5.14 (2H,s); 3.90 (3H,s); 3.78 (3H,s).

;~
, . ~.

:~:

.. ~::
. ~
.~: ' .,, ::
:
: . : ~, -~ " 13~0~3 02 Procedure 2 04 3-BenzvloxY-1,2-bishydroxvmethYlbenzene l3 cu20u 12 To a suspenslon of lOg of lithium aluminium hydride in 13 300ml of dry diethyl ether was added dropwise a 14 solution of 18g (60mmol) of dimethyl 3-benzyloxy phthalate in 125ml of dry diethyl ether.

17 After heating under reflux for 4 hours the mlxture was ~18 cooled and treated sequentially with lOml of water, 10 19 ml of 10% sodium hydroxide solution and 20ml of water.
The resultant mixture was filtered and the filtrate 21 evaporated to yield the title compound as a pale yellow 22 oil.

24 lH-nmr 6 ~CDCl~):
~26 7.6-7.1 (6H,m); 7.0-6.8 (2H,m); 5.0q (2H,s); 4.76 27 (2H,s); 4.55 (2H,s); 3.8-3.3 ~2H,broad signal, 28 exchanges with D20).
~ 29 `::~

`` 1 ~ 3 ` - -02 Procedure 3 04 3-BenzyloxY-1,2-blsbromomethvlbenzene 08 ~ CH2Br i ~11 CH2Br i 13 To a solution of 12g (49.2mmol) of 3-benzyloxy-1,2-14 bishydroxymethylbenzene in 350ml of dry dlethyl ether at 5C was added dropwise 30ml t252mmol~ of phosphorus 16 tribromide in 50ml of dry diethyl ether. After 17 stirring at room temperature for 14 hours the mixture 18 was poured onto 500g of ice, the organic layer was 19 separated, washed with 200ml of water, 200ml of saturated sodium bicarbonate solution and 200ml of 21 brlne. Drylng and evaporatlon of the resultant organic -~
22 phase gave the tltle compound as a whlte solid.

24 lH-nmr 6 (CDC13):

; 26 7.7-7.1 (6H,m); 7.1-6.9 (2H,m); 5.17 (2H,s); 4.86 ~;
27 (2H,s); 4.65 (2H,s).

~. '. ~

;' ~

!~
' ' ` `~
1330~

02 Procedure 4 04 2H-~4-Benzyloxv-1,3-dihydroisoindole)acetonitrile ~ 10 ¢~N--C~12CN
~ 11 13 To a mlxture of 5.14g (55.5mmol) of aminoacetonltrile 14 hydrochloride and 18.3ml (l34mmol) of triethylamine in 15 75ml of dry dimethylformamide at 50C was added 16 dropwise a solution of 15g (40.5mmol) of 17 3-benzyloxy-1,2- bisbromomethylbenzene in 50ml of dry 18 dimethylformamide. The temperature was maintained at 19 50C for 3 hours. After stirring at room temperature 20 for 14 hours the mixture was poured into 500ml of 21 water. The resultant aqueous phase was extracted three 22 times with 150ml portions of diethyl ether. The 23 combined organic layers were drled and evaporated to 24 yield a pale yellow oll. `
26 lH-nmr ~CDCl~):

28 7.5-6.6 (8H,m); 5.00 (2H,s); 4.03 (4H,s) 3.68 (2H,s) . .
, : ~
:

` ~ 133~^3 02 Procedure 5 ~ 2H- l 4-Benzyloxy-7-chloro-l, 3-dihYdroisoindole ) 05 acetonltrlle ¢~--CH2CN

12 Cl 14 To a solution of 6.9g (26.lmmol) of 2H-(3-benzloxy-1,3-dlhydroisolndole)acetonitrile in 70ml of 16 dichloromethane at room temperature was added 2.lml 17 (26.1mmol) of sulphuryl chloride. After stirring for 18 0.5 hours a further 2.lml of sulphuryl chloride was 19 added. The mixture was stirred for 1 hour after which 20 . the solvent was evaporated. The resultant mixture was 21 partitioned between saturated sodium bicarbonate 22 solution and dichloromethane. The organic phase was 23 separated, dried and evaporated to yleld the crude 24 product. Chromatography over silica gel, eluting with dichloromethane, gave the title compound as a pale 26 yellow oil.

28 lH-nmr ~ ~CDCl~:

7.5-7.1 (5H,m); 7.01 (lH,d); 6.50 (lH,d); 4.88 (2H,S~
31 4.02 (4H,s); 3.65 (2H,s).

~' ,:~
.~ :
.,~

, i ;,~;~1 33066~

02 Procedure 6 04 2H- (7-Chloro-4-hydroxy-l,3-dihydroisoindole)-05 acetonitrile ~N--CH2CN

12 Cl 14 To a solution of 3.2g (10.7mmol) of 2H-(4-benzloxy-7-chloro-1,3-dlhydroisoindole)acetonitrile in 40ml of 16 dichloromethane at room temperature, under an 17 atmosphere of nitrogen, was added 15.6ml (120mmol) of 18 boron trifluoride dimethylsulphide complex. After 19 stirring for 3 hours the mixture was poured into water. The resultant aqueous phase was neutralised 21 with solid sodium bicarbonate and extracted ~4 x lOOml 22 aliquots) with dichloromethane. The combined organic 23 extracts were dried and evaporated to yield the crude 24 product. Chromatography over silica gel, eluting with dichloromethane/methanol (0->2%), gave the title 26 compound.

28 lH_nmr ~ (cDcl~):

6.95 (lH,d); 6.60 (lH,s exchanges with D~O); 6.48 31 (lH,d); 4.05 (4H,s); 3.73 (2H,s).

"

133~6~
~D

02 Procedure 7 04 2H- r 7-Chloro-4-t3-methYlbut-2-envloxy~-1,3-05 dihydroisoindolelacetonitrile 07 "~

cu2cl~

14 A mixture of 0.8g ~3.8mmol) of 2H-(7-chloro-4-hydroxy-l~3-dihydroisoindole)acetonitrlle and l.Og 16 (7.2mmol) of anhydrous potassium carbonate in 20ml of 17 butanone was heated under reflux wlth stlrring for 1 18 hour. The mixture was cooled to room temperature and 19 0.62g (3.8mmol~ of 90% 1-bromo-3-methylbut-2-ene was added. Heatin~ was recommenced and continued for 16 21 hours after which time the mlxture was cooled and ~
22 evaporated to dryness. The residue was partltioned 23 between dichloromethane and water, the organic layer 24 was separated and dried to yield the tltle compound as an oil.
~6 27 lH-nmr ~ ( CDCl~
:

29 7.10 (lH,d); 6.67 tlH,d); 5.42 (lH,t); 4.50 ~2H,d);

4.03 (4H,s); 3.68 (2H,s); 1.80 (3H,s~; 1.76 (3H,s).
31 -~

' ,, .q '~f ~i .,~ .

~ ~,"I~;V,,,;,~ ","

:3 ~
, .~ .
133~3 02 Procedure 8 04 2H- r 7-Chloro-4-(3-methvlbutYloxv~ 3-dihYdro-Os isoindolelacetonitrile.

j~Cll~C~

14 2H-(7-Chloro-4-hydroxy-1,3-dihydroisoindole) acetonitrile, 2.12g (8.65mmol) in 25ml of dry 16 dimethylformamide (DMF) was added to a suspension of 17 0.69g (17.25mmole`) of 60% sodium hydride in lOml of 18 DMF. After stlrring at room temperature for 0.25h and 19 cooling to 5C, l-bromo-3- methylbutane, lml (8.35mmol)~ in 5ml of DMF was added. The reaction 21 mixture was stirred overnight at room temperature, 22 poured into lOOml of water and then extracted twice, 23 each time with lOOml portlons of dlethyl ether. The 24 organlc layer was dried and evaporated to yield the title compound as a light brown oil.

27 lH-nmr ~ ICDCl~):

29 7.12 (lH, d); 6.66 (lH, d); 4.11 (4H, s); 4.0-3.9 (2H, m); 3.75 (2H, s); 2.0-1.5 (3H, m); 0.94 (6H, d).

~, ., i.
~, 02 Pharmacoloqical Data 04 Demonstration of the Pharmacological Selectivity for 05 Pre- and Post-junctional a~=Adrenoceptors. _ 07 To determine post-junctional a2-adrenoceptor activity, 08 ring segments of rabbit lateral saphenous vein were 09 mounted in organ baths at 37C containing Krebs medium. Contractions of this tissue in response to 11 noradrenaline are mediated via post-junctional 12 a2-adrenoceptors (Alabaster et al, 1985) and therefore 13 the ability of a2-adrenoceptor antagonists to 14 pharmacologically antagonise such contractions gives a quantitive measure of the activity of compounds for 16 this receptor subtype.

18 Pre-~unctional actlvity is estimated by the ability of 19 a2-adrenoceptor antagonists to reverse a clonidine-induced inhibition of t3H]-noradrenaline 21 release from segments of rabbit aorta. Rings of rabbit 22 abdominal aorta were incubated at 37C in Krebs medium 23 containin~ ~0 ~Ci of ~3H]-noradrenaline (specific 24 activity 10-30Ci/mmol) for 1 hour. Tissues were then mounted vertically between parallel platinum electrodes 26 and superfused with tritium-free Krebs medium.
27 Electrical stimulation was carried out using square 28 wave pulses of 0.5 msec duration and lOOV were 29 delivered to the tissues at a frequency of 2Hz. The superfusate was collected in 3 minute fractions. Six 31 stimuli (Sl-S6) were applied to each tissue. Clonidine 32 was added to the superfusion stream after S2 at a 33 concentration of O.Ol~M and again after S3 at a 34 concentration of O.l~M. Each antagonist added after S4 and a further concentration of clonidine (l~M) infused 36 after S5. At the end of each experiment each aortic , ~
J

~:

~-~; - 13~6~

02 segment solubilised in 150~1 of FisosolveR tissue 03 solubiliser and the radioactivity of both superfusate 04 samples and aortic rings determined by liquid 05 scintillation spectroscopy.

07 Results are calculated by the method of Docherty et al, 08 1982, with stimulation evoked overflow of tritium o9 expressed as a percentage of the tritium content of the tissue at- the onset of the respective stimulation 11 period.

13 Example Post-synaptic Pre-synaptic 14 Number PA~ PA~
16 1 6.6 <5.0 i~ 17 2 6.7 5.4 i 19 Alabaster V.A., Xeir R.F. and Peters C.J. (1985) Naunun-Schmiedeberg's Arch Pharmacol 330, 33-36.
~ 21 Docherty J.R., Gothert M., Dieckhoffer C. and Starke 22 K. (1982) Arzneim-Forsch, Drug Res., 32, 1534-1540.
;~ 23 .
, ,~ l '' ;~ '`

~ .
.,~
'~

Claims

1. A compound of formula (I):

(I) or a pharmaceutically acceptable salt thereof, wherein:

R1 and R2 may each represent hydrogen or C1-12 alkyl providing that at least one of R1 or R2 represents alkyl;
R3 and R4 each represent hydrogen or R3 and R4 together represent a bond;
n represents an integer 1 or 2;
and m represents an integer 1 or 2.

2. A compound according to claim 1, wherein R1 and R2 each represent C1-6 alkyl.

3. A compound according to claim 1, wherein R1 and R2 each represent methyl.

4. A compound according to claim 1, wherein R3 and R4 each represent hydrogen.

5. A compound according to claim 1, wherein R3 and R4 together represent a bond.

6. A compound according to claim 1, wherein n represents 1.

7. A compound according to claim 1, wherein m represents 1.

8. 2-(2H-[7-chloro-4-(3-methylbut-2-enyloxy)-1,3-dihydro-isoindole]methyl)-4,5-dihydroimidazole or a pharmaceutically acceptable salt thereof.

9. 2-(2H-[7-chloro-4-(3-methylbutyloxy)-1,3-dihydro-isoindole]methyl)-4,5-dihydroimidazole or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor.

11. The use of an effective, non-toxic, amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the treatment and/or prophylaxis of hyperglycaemia in a human or non-human mammal.

12. The use of an effective non-toxic amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the treament and/or prophylaxis of hypertension and/or inhibiting blood platelet aggregation in a human or non-human mammal.